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J. Biol. Chem. 277 (49): 47373-47379

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

A CD36-initiated Signaling Cascade Mediates Inflammatory Effects of beta -Amyloid*

Kathryn J. MooreDagger , Joseph El Khoury§, Lea A. MedeirosDagger , Kinya Terada, Changiz Geula||, Andrew D. Luster§, and Mason W. FreemanDagger **

From the Dagger  Lipid Metabolism Unit, § Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology, and the  Neurosurgical Service, Massachusetts General Hospital, Harvard Medical School and || Division of Aging, Beth Israel Deaconess Medical Center, Boston, Massachusetts, 02114

beta -Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar beta -amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, beta -amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to beta -amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by beta -amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance.


* This work was supported by National Institutes of Health Grants R01AG20255-01 (to K. J. M.), P01 DK50305 (to M. W. F. and A. D. L.), R01 HL45098 (to M. W. F.), and NS41330-02 (to J. E. K.) and a grant from the Alzheimer's Disease Research Program of the American Health Assistance Foundation (to J. E. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

** To whom correspondence should be addressed: Lipid Metabolism Unit, Massachusetts General Hospital, 55 Fruit St., GRJ 1328, Boston, MA 02114. Tel.: 617-726-5906; E-mail: Freeman@molbio.mgh.harvard.edu.


Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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